Modulators of the glucocorticoid receptor and method

ABSTRACT

Novel non-steroidal compounds are provided which are glucocorticoid receptor modulators which are useful in treating diseases requiring glucocorticoid receptor agonist or antagonist therapy such as obesity, diabetes, inflammatory and immune disorders, and have the structure 
                         
where A, B, and R 1 -R 6  are defined herein.

This application claims priority to U.S. Provisional Application60/477,545 filed Jun. 11, 2003, the entirety of which is incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to new non-steroidal compounds which areglucocorticoid receptor (GR) modulators (that is agonists andantagonists) and thus are useful in treating diseases requiringglucocorticoid receptor agonist or antagonist therapy such as obesity,diabetes and inflammatory or immune associated diseases, and to a methodfor using such compounds to treat these and related diseases.

BACKGROUND OF THE INVENTION

The nuclear hormone receptor (NHR) family of transcription factors bindlow molecular weight ligands and either stimulate or represstranscription. See, e.g., V. LAUDET ET AL., THE NUCLEAR RECEPTOR FACTSBOOK, 345, (2002). NHRs stimulate transcription by binding to DNA andinducing transcription of specific genes. NHRs may also stimulatetranscription by not binding to DNA itself, rather they-may modulate theactivity of other DNA binding proteins. Stocklin, E., et al., Nature383:726-8 (1996). The process of stimulation of transcription is calledtransactivation. NHRs repress transcription by interacting with othertranscription factors or coactivators and inhibiting the ability ofthese other transcription factors or coactivators from inducingtranscription of specific genes. This repression is calledtransrepression. For a review of this topic, see generally V. Laudet,supra, beginning at 42.

The glucocorticoid receptor (GR) is a member of the nuclear hormonereceptor family of transcription factors, and a member of the steroidhormone family of transcription factors. Affinity labeling of theglucocorticoid receptor protein allowed the production of antibodiesagainst the receptor which facilitated cloning the glucocorticoidreceptors. For results in humans see Weinberger, et al., Science 228,640-742, (1985); Weinberger, et al., Nature, 318, 670-672 (1986) and forresults in rats see Miesfeld, R., Nature, 312, 779-781, (1985).

Glucocorticoids which interact with GR have been used for over 50 yearsto treat inflammatory diseases. It has been clearly shown thatglucocorticoids exert their anti-inflammatory activity via theinhibition by GR of the transcription factors NF-kappaB and AP-1. Thisinhibition is termed transrepression. It has been shown that the primarymechanism for inhibition of these transcription factors by GR is via adirect physical interaction. This interaction alters the transcriptionfactor complex and inhibits the ability of NF-kappaB and AP-1 tostimulate transcription. See Jonat, C., et al., Cell, 62, 1189 (1990);Yang-Yen, H. F., et al,. Cell, 62, 1205 (1990); Diamond, M. I. et al.,Science 249, 1266 (1990); and Caldenhoven, E. et al., Mol. Endocrinol.,9, 401 (1995). Other mechanisms such as sequestration of co-activatorsby GR have also been proposed. See Kamer Y, et al., Cell, 85, 403(1996); and Chakravarti, D. et al., Nature, 383, 99 (1996). NF-kappaBand AP-1 play key roles in the initiation and perpetuation ofinflammatory and immunological disorders. See Baldwin, A S, Journal ofClin. Investigation, 107, 3 (2001); Firestein, G. S., and Manning, A.M., Arthritis and Rheumatism, 42, 609 (1999); and Peltz, G., Curr. Opin,in Biotech. 8, 467 (1997). NF-kappaB and AP-1 are involved in regulatingthe expression of a number of important inflammatory andimmunomodulatory genes including: TNF-alpha, IL-1, IL-2, IL-5, adhesionmolecules (such as E-selectin), chemokines (such as Eoxtaxin andRantes), Cox-2, and others.

In addition to causing transrepression, the interaction of aglucocorticoid with GR can cause GR to induce transcription of certaingenes. This induction of transcription is termed transactivation.Transactivation requires dimerization of GR and binding to aglucocorticoid response element (GRE).

Recent studies using a transgenic GR dimerization defective mouse whichcannot bind DNA have shown that the transactivation (DNA binding)activities of GR could be separated from the transrepressive (non-DNAbinding) effect of GR. These studies also indicate that many of the sideeffects of glucocorticoid therapy are due to the ability of GR to inducetranscription of various genes involved in metabolism, whereas,transrepression, which does not require DNA binding leads to suppressionof inflammation. See Tuckermann, J. et al., Cell, 93, 531 (1998) andReichardt, H M, EMBO J., 20, 7168 (2001).

The art is in need of modulators of NHRs. A modulator of an NHR may beuseful in treating NHR-associated diseases, that is diseases associatedwith the expression products of genes whose transcription is stimulatedor repressed by NHRs. For instance, the art is in need of modulators ofNHRs that inhibit AP-1 and NFκB, as such compounds would be useful inthe treatment of inflammatory and immune diseases and disorders such asosteoarthritis, rheumatoid arthritis, multiple sclerosis, asthma,inflammatory bowel disease, transplant rejection and graft vs. hostdisease.

Particularly concerning GR, although glucocorticoids are potentanti-inflammatory agents, their systemic use is limited by side effects.A compound that retained the anti-inflammatory efficacy ofglucocorticoids while minimizing the side effects such as diabetes,osteoporosis and glaucoma would be of great benefit to a very largenumber of patients with inflammatory diseases.

Additionally concerning GR, the art is in need of compounds thatantagonize transactivation. Such compounds may be useful in treatingmetabolic diseases associated with increased levels of glucocorticoid,such as diabetes, osteoporosis and glaucoma.

Additionally concerning GR, the art is in need of compounds that causetransactivation. Such compounds may be useful in treating metabolicdiseases associated with a deficiency in glucocorticoid. Such diseasesinclude Addison's disease.

SUMMARY OF THE INVENTION

In accordance with the present invention, a method is provided forpreventing or inhibiting the onset of or treating a GR-associateddisease which is associated with the expression product of a gene whosetranscription is stimulated or repressed by glucocorticoid receptors,which comprises administering to a patient in need of treatment atherapeutically effective amount of a compound having formula (I),

including all stereoisomers, salts, solvates or prodrugs thereof,wherein:

-   A and B are independently cycloalkyl, aryl or heteroaryl, each of    which is optionally substituted;-   R¹ is    -   (i) hydrogen, COR⁹, CO₂R⁹, SO₂R⁹, S(O)R⁹ or CONR⁷R⁸; or    -   (ii) C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, aryl, arylalkyl,        heteroaryl or heteroarylalkyl, each group of which is optionally        substituted;-   R², R³ and R⁴ are independently hydrogen, C₁₋₆alkyl,    C₁₋₆heteroalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl or heteroaryl, each    group of which is optionally substituted where valence allows;-   R⁵ and R⁶ are independently    -   (i) hydrogen, F, Cl, Br, I, NO₂, CN, OR⁷, NR⁷R⁸, SR⁷, COR⁹,        CO₂R⁹ or CONR⁷R⁸; or    -   (ii) C₁₋₆alkyl, C₁₋₆heteroalkyl, C₃₋₈cycloalkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, aryl, heteroaryl, heteroarylalkyl or arylalkyl,        each group of which is optionally substituted;-   R⁷ and R⁸ are independently    -   (i) hydrogen, COR⁹, SO₂R⁹ or S(O)R⁹; or    -   (ii) C₁₋₆alkyl, C₁₋₆heteroalkyl C₁₋₆haloalkyl, aryl, heteroaryl,        heteroarylalkyl or arylalkyl, each group of which is optionally        substituted; and-   R⁹ is hydrogen, C₁₋₆alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl,    heteroarylalkyl or arylalkyl,    wherein each occurrence of R⁷, R⁸ and/or R⁹ is chosen independently.

Another aspect of the invention provides compounds within the scope ofFormula (I), including all stereoisomers, salts, solvates or prodrugsthereof, wherein:

-   A and B are independently aryl or heteroaryl, each of which is    optionally substituted provided:    -   (i) A is not benz[c,d]indole;    -   (ii) R³ or R⁴ is not

-   -    if the other of R³ or R⁴ is hydrogen; and    -   (iii) formula (I) is not

In another aspect of the present invention, there is providedpharmaceutical compositions useful in treating endocrine disorders,rheumatic disorders, collagen diseases, dermatologic disease, allergicdisease, ophthalmic disease, respiratory disease, hematologic disease,gastrointestinal disease, inflammatory disease, autoimmune disease,diabetes, obesity, and neoplastic disease, as well as other uses asdescribed herein, which includes a therapeutically effective amount(depending upon use) of a compound of formula (I) of the invention and apharmaceutically acceptable carrier.

In still another aspect, the present invention provides a method ofpreventing, inhibiting onset of or treating endocrine disorders,rheumatic disorders, collagen diseases, dermatologic disease, allergicdisease, ophthalmic disease, respiratory disease, hematologic disease,gastrointestinal disease, inflammatory disease, autoimmune disease,diabetes, obesity, and neoplastic disease, GR-associated diseases, thatis a disease associated with the expression product of a gene whosetranscription is stimulated or repressed by GR or a disease associatedwith GR transactivation, including inflammatory and immune diseases anddisorders as described hereinafter, which includes the step ofadministering a therapeutically effective amount of a compound offormula (I) of the invention to a patient in need of treatment.

Another aspect of the present involves a method for preventing,inhibiting onset of or treating a disease associated with AP-1- and/orNFκB-dependent gene expression, that is a disease associated with theexpression of a gene under the regulatory control of AP-1 and/or NFκBsuch as inflammatory and immune disorders, cancer and tumor disorders,such as solid tumors, lymphomas and leukemia, and fungal infections suchas mycosis fungoides.

DETAILED DESCRIPTION

The present invention relates to new non-steroidal compounds which areglucocorticoid receptor (GR) modulators (that is agonists andantagonists) and thus are useful in treating diseases requiringglucocorticoid receptor agonist or antagonist therapy such as obesity,diabetes and inflammatory or immune associated diseases, and to a methodfor using such compounds to treat these and related diseases.

The term “disease associated with GR transactivation,” as used herein,refers to a disease associated with the transcription product of a genewhose transcription is transactivated by a GR. Such diseases include,but are not limited to: osteoporosis, diabetes, glaucoma, muscle loss,facial swelling, personality changes, hypertension, obesity, depression,and AIDS, the condition of wound healing, primary or secondaryandrenocortical insufficiency, and Addison's disease.

The term “treat”, “treating”, or “treatment,” in all grammatical forms,as used herein refers to the prevention, reduction, or amelioration,partial or complete alleviation, or cure of a disease, disorder, orcondition.

The terms “glucocorticoid receptor” and “GR,” as used herein, refereither to a member of the nuclear hormone receptor family oftranscription factors which bind glucocorticoids and either stimulate orrepress transcription, or to GR-beta. These terms, as used herein, referto glucocorticoid receptor from any source, including but not limitedto: human glucocorticoid receptor as disclosed in Weinberger, et al.,Science 228, 640-742 (1985) and in Weinberger, et al., Nature, 318,670-672 (1986); rat glucocorticoid receptor as disclosed in Miesfeld,R., Nature, 312, 779-781 (1985); mouse glucocortoid receptor asdisclosed in Danielson, M. et al., EMBO J., 5, 2513; sheepglucocorticoid receptor as disclosed in Yang, K., et al., J. Mol.Endocrinol., 8, 173-180 (1992); marmoset glucocortoid receptor asdisclosed in Brandon, D. D., et al, J. Mol. Endocrinol., 7, 89-96(1991); and human GR-beta as disclosed in Hollenberg, S M. et al.,Nature, 318, 635 (1985), Bamberger, C. M. et al., J. Clin Invest. 95,2435 (1995).

The term, “disease associated with AP-1-dependent gene expression,” asused herein, refers to a disease associated with the expression productof a gene under the regulatory control of AP-1. Such diseases include,but are not limited to: inflammatory and immune diseases and disorders;cancer and tumor disorders, such as solid tumors, lymphomas andleukemia; and fungal infections such as mycosis fungoides.

The term “inflammatory or immune associated diseases or disorders” isused herein to encompass any condition, disease, or disorder that has aninflammatory or immune component, including, but not limited to, each ofthe following conditions: transplant rejection (e.g., kidney, liver,heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, smallbowel, skin allografts, skin homografts (such as employed in burntreatment), heart valve xenografts, serum sickness, and graft vs. hostdisease, autoimmune diseases, such as rheumatoid arthritis, psoriaticarthritis, multiple sclerosis, Type I and Type II diabetes, juvenilediabetes, obesity, asthma, inflammatory bowel disease (such as Crohn'sdisease and ulcerative colitis), pyoderma gangrenum, lupus (systemiclupus erythematosis), myasthenia gravis, psoriasis, dermatitis,dermatomyositis; eczema, seborrhoea, pulmonary inflammation, eyeuveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, autoimmunethyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth), perniciousor immunohaemolytic anaemia, atherosclerosis, Addison's disease(autoimmune disease of the adrenal glands), idiopathic adrenalinsufficiency, autoimmune polyglandular disease (also known asautoimmune polyglandular syndrome), glomerulonephritis, scleroderma,morphea, lichen planus, viteligo (depigmentation of the skin), alopeciagreata, autoimmune alopecia, autoimmune hypopituatarism, Guillain-Barresyndrome, and alveolitis; T-cell mediated hypersensitivity diseases,including contact hypersensitivity, delayed-type hypersensitivity,contact dermatitis (including that due to poison ivy), uticaria, skinallergies, respiratory allergies (hayfever, allergic rhinitis) andgluten-sensitive enteropathy (Celiac disease); inflammatory diseasessuch as osteoarthritis, acute pancreatitis, chronic pancreatitis, acuterespiratory distress syndrome, Sezary's syndrome and vascular diseaseswhich have an inflammatory and or a proliferatory component such asrestenosis, stenosis and artherosclerosis. Inflammatory or immuneassociated diseases or disorders also includes, but is not limited to:endocrine disorders, rheumatic disorders, collagen diseases,dermatologic disease, allergic disease, ophthalmic disease, respiratorydisease, hematologic disease, gastrointestinal disease, inflammatorydisease, autoimmune disease, congenital adrenal hyperplasia,nonsuppurative thyroiditis, hypercalcemia associated with cancer,juvenile rheumatoid arthritis, Ankylosing spondylitis, acute andsubacute bursitis, acute nonspecific tenosynovitis, acute goutyarthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis,epicondylitis, acute rheumatic carditis, pemphigus, bullous dermatitisherpetiformis, severe erythema multiforme, exfoliative dermatitis,seborrheic dermatitis, seasonal or perennial allergic rhinitis,bronchial asthma, contact dermatitis, atopic dermatitis, drughypersensitivity reactions, allergic conjunctivitis, keratitis, herpeszoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, opticneuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonarytuberculosis chemotherapy, idiopathic thrombocytopenic purpura inadults, secondary thrombocytopenia in adults, acquired (autoimmune)hemolytic anemia, leukemias and lymphomas in adults, acute leukemia ofchildhood, regional enteritis, autoimmune vasculitis, multiplesclerosis, chronic obstructive pulmonary disease, solid organ transplantrejection, sepsis.

In addition, in accordance with the present invention a method oftreating a disease associated with AP-1-induced or NFκB-inducedtranscription is provided wherein a compound of formula (I) of theinvention is administered to a patient in need of treatment in atherapeutically effective amount to induce NHR transrepression of theAP-1-induced or NFκB-induced transcription, thereby treating thedisease.

Other therapeutic agents, such as those described hereafter, may beemployed with the compounds of the invention in the present methods. Inthe methods of the present invention, such other therapeutic agent(s)may be administered prior to, simultaneously with or following theadministration of the compound(s) of the present invention.

In a particular embodiment, the compounds of the present invention areuseful for the treatment of the aforementioned exemplary disordersirrespective of their etiology, for example, for the treatment oftransplant rejection, rheumatoid arthritis, inflammatory bowel disease,and viral infections.

Preferred compounds include compounds within the scope of formula (I)(above), stereoisomers, salts, solvates or prodrugs thereof, wherein:

-   A is phenyl preferably substituted by hydrogen, F, Cl, Br, I, NO₂,    CN, OR⁷, SR⁷, C₁₋₆alkyl, or C₁₋₆heteroalkyl; or-   R², R³ and R⁴ are independently hydrogen, C₁₋₆alkyl,    C₁₋₆heteroalkyl, arylC₁₋₆ alkyl, heteroarylC₁₋₆ alkyl, C₂₋₆alkenyl,    and C₂₋₆alkynyl, wherein the heteroaryl or aryl component of the    arylC₁₋₆ alkyl and heteroarylC₁₋₆ alkyl groups is optionally    substituted

Alternatively preferred compounds are described by formula (II),

including all stereoisomers, salts, solvates or prodrugs thereof,wherein:

-   B is aryl or heteroaryl, each of which is optionally substituted;-   R¹ is    -   (i) hydrogen, COR⁹, CO₂R⁹, SO₂R⁹, S(O)R⁹ or CONR⁷R⁸; or    -   (ii) C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, each group of which is optionally        substituted;-   R², R³ and R⁴ are independently hydrogen, C₁₋₆alkyl,    C₁₋₆heteroalkyl, arylC₁₋₆ alkyl, heteroarylC₁₋₆ alkyl, C₂₋₆alkenyl,    and C₂₋₆alkynyl, wherein the heteroaryl or aryl component of the    arylC₁₋₆ alkyl and heteroaryl C₁₋₆ alkyl groups is optionally    substituted-   R⁷ and R⁸ are independently    -   (i) hydrogen, COR⁹, SO₂R⁹ or S(O)R⁹    -   (ii) C₁₋₆alkyl, C₁₋₆heteroalkyl C₁₋₆haloalkyl, aryl, heteroaryl,        allyl, arylalkyl, each group of which is optionally substituted;-   T¹ through T⁵ are independently    -   (i) hydrogen, F, Cl, Br, I, NO₂, CN, OR⁹ or SR⁹; or    -   (ii) C₁₋₆alkyl or C₁₋₆heteroalkyl, each group of which is        optionally substituted; and-   R⁹ is hydrogen, C₁₋₆alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl    or arylalkyl; provided that formula (II) is not

Compounds within the scope of formula (II) that are more preferred arethose in which

-   B is an optionally substituted phenyl ring, (especiallya phenyl ring    substituted by hydrogen F, Cl, Br, I, NO₂, CN, OR⁷, SR⁷, C₁₋₆alkyl,    or C₁₋₆heteroalkyl); or-   R¹ is hydrogen or C₁₋₆alkyl; or-   T¹ through T⁵ is independently selected from H, F, Cl, Br, I, or    —OC₁₋₆alkyl.

Alternatively, preferred compounds are those described by formula (I),

including all stereoisomers, salts, solvates or prodrugs thereof,wherein:

-   R³ and R⁴ are independently hydrogen, C₁₋₆alkyl, C₁₋₆heteroalkyl,    C₁₋₆arylalkyl, C₁₋₆heteroarylalkyl C₂₋₆alkenyl, C₂₋₆alkynyl or    allyl, wherein the heteroaryl or aryl component of the    C₁₋₆heteroarylalkyl and C₁₋₆arylalkyl groups is optionally    substituted.-   T¹ through T¹⁰ are independently    -   (i) hydrogen, F, Cl, Br, I, NO₂, CN, OR⁹ or SR⁹; or    -   (ii) C₁₋₆alkyl or C₁₋₆heteroalkyl, each group of which is        optionally substituted; and-   R⁹ is hydrogen, C₁₋₆alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl    heteroarylalkyl or arylalkyl;-   provided that if T⁸ is fluoro and T⁶, T⁷, T⁹ and T¹⁰ are all    hydrogen then T¹ and T³ cannot both be chloro if T², T⁴, and T⁵ are    all hydrogen.

Compounds that are more preferred within the scope of formula (III) arethose in which

-   T¹ through T¹⁰ are selected independently from hydrogen, F, Cl, Br    I., and —OC₁₋₆alkyl; or-   R³ and R⁴ are selected independently from hydrogen and C₁₋₆alkyl.

Especially preferred compounds within the scope of formula (III) arethose in which R³ is hydrogen and R⁴ is C₁₋₆alkyl.

Other preferred are compounds selected from the following:

-   (i)

-   -   (iii) or a stereoisomer, salt, solvate or prodrug of (i)        thereof.

Pharmaceutical of the present invention are compositions comprising acompound as defined in formulas (I), (II) or (III) as described aboveand a pharmaceutically acceptable carrier therefor.

Preferred pharmaceutical combinations of the present invention comprisea compound as defined in (I), (II) or (III) as described above and animmunosuppressant, an anticancer agent, an anti-viral agent, ananti-inflammatory agent, an anti-fungal agent, an anti-biotic, ananti-vascular hyperproliferation agent, an anti-depressant agent, alipid-lowering agent, a lipid modulating agent, an antidiabetic agent,an anti-obesity agent, an antihypertensive agent, a platelet aggregationinhibitor and/or an antiosteoporosis agent, wherein

-   the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl    urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γ dual    agonist, an SGLT2 inhibitor, a DP4 inhibitor, an aP2 inhibitor, an    insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin    and/or a meglitinide;-   the anti-obesity agent is a beta 3 adrenergic agonist, a lipase    inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid    receptor agonist, an aP2 inhibitor or an anorectic agent;-   the lipid lowering agent is an MTP inhibitor, an HMG CoA reductase    inhibitor, a squalene synthetase inhibitor, a fibric acid    derivative, an upregulator of LDL receptor activity, a lipoxygenase    inhibitor or an ACAT inhibitor; and-   the antihypertensive agent is an ACE inhibitor, angiotensin II    receptor antagonist, NEP/ACE inhibitor, calcium channel blocker or    β-adrenergic blocker.

Especially preferred combinations are those wherein

-   the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide,    glimepiride, glipyride, glipizide, chlorpropamide, gliclazide,    acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone,    insulin, G1-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440,    R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242,    GW-409544, KRP297, AC2993, LY315902, P32/98 and/or NVP-DPP-728A;-   the anti-obesity agent is selected from orlistat, ATL-962, AJ9677,    L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine,    phentermine, phenylpropanolamine, and/or mazindol;-   the lipid lowering agent is pravastatin, lovastatin, simvastatin,    atorvastatin, cerivastatin, fluvastatin, itavastatin, visastatin,    fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700,    cholestagel, niacin and/or LY295427;-   the antihypertensive agent is an ACE inhibitor which is captopril,    fosinopril, enalapril, lisinopril, quinapril, benazepril,    fentiapril, ramipril or moexipril; an NEP/ACE inhibitor which is    omapatrilat,    [S[(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-acetic    acid (gemopatrilat) or CGS 30440 or an angiotensin II receptor    antagonist which is irbesartan, losartan or valsartan; amlodipine    besylate, prazosin HCl, verapamil, nifedipine, nadolol, propranolol,    carvedilol or clonidine HCl; and-   the platelet aggregation inhibitor is aspirin, clopidogrel,    ticlopidine, dipyridamole or ifetroban.

Even more preferred combinations are those wherein

-   the immunosuppressant is a cyclosporin, mycophenolate,    interferon-beta, deoxyspergolin, FK-506 or Ant.-IL-2;-   the anti-cancer agent is azathiprine, 5-fluorouracel,    cyclophosphamide, cisplatin, methotrexate, thiotepa, or carboplatin;-   the anti-viral agent is abacavir, aciclovir, ganciclovir, zidanocin,    or vidarabine; and-   the antiinflammatory drug is ibuprofen, celecoxib, rofecoxib,    aspirin, naproxen, ketoprofen, diclofenac sodium, indomethacin,    piroxicam, prednisone, dexamethasone, hydrocortisone, or    triamcinolone diacetate.

In accordance with the present invention, methods are provided forpreventing or inhibiting the onset of or treating a GR-associateddisease which is associated with the expression product of a gene whosetranscription is stimulated or repressed by glucocorticoid receptors,which comprises administering to a patient in need of treatment atherapeutically effective amount of a compound having formulas (I), (II)or (III) as described above.

Preferred methods are those in which the GR-associated disease is aninflammatory or immune associated disease or disorder which is anendocrine disorder, rheumatic disorder, collagen disease, dermatologicdisease, allergic disease, ophthalmic disease, respiratory disease,hematologic disease, gastrointestinal disease, inflammatory disease,autoimmune disease, neoplastic disease and metabolic disease.

Especially preferred are methods wherein the inflammatory or immuneassociated disease or disorder is transplant rejection of kidney, liver,heart, lung, pancreas, bone marrow, cornea, small bowel, skinallografts, skin homografts, heart valve xenograft, serum sickness, andgraft vs. host disease, rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, Type I and Type II diabetes, juvenile diabetes,obesity, asthma, inflammatory bowel disease, Crohn's disease, ulcerativecolitis, pyoderma gangrenum, systemic lupus erythematosis, myastheniagravis, psoriasis, dermatitis, dermatomyositis; eczema, seborrhoea,pulmonary inflammation, eye uveitis, hepatitis, Grave's disease,Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's or Sjorgen'ssyndrome, pernicious or immunohaemolytic anaemia, atherosclerosis,Addison's disease, idiopathic adrenal insufficiency, autoimmunepolyglandular disease, glomerulonephritis, scleroderma, morphea, lichenplanus, viteligo, alopecia greata, autoimmune alopecia, autoimmunehypopituatarism, Guillain-Barre syndrome, and alveolitis; contacthypersensitivity, delayed-type hypersensitivity, contact dermatitis,uticaria, skin allergies, respiratory allergies, hayfever, allergicrhinitis and gluten-sensitive enteropathy, osteoarthritis, acutepancreatis, chronic pancreatitis, acute respiratory distress syndrome,Sezary's syndrome, restenosis, stenosis and artherosclerosis, congenitaladrenal hyperplasia, nonsuppurative thyroiditis, hypercalcemiaassociated with cancer, juvenile rheumatoid arthritis, Ankylosingspondylitis, acute and subacute bursitis, acute nonspecifictenosynovitis, acute gouty arthritis, post-traumatic osteroarthritis,synovitis of osteoarthritis, epicondylitis, acute rheumatic carditis,pemphigus, bullous dermatitis herpetitformis, severe erythemamultiforme, exfoliative dermatitis, psoriasis, seborrheic dermatitis,seasonal or perennial allergic rhinitis, bronchial asthma, contactdermatitis, atopic dermatitis, drug hypersensitivity reactions, allergicconjuncivitis, keratitis, herpes zoster ophthalmicus, iritis andiridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis,fulminating or disseminated pulmonary tuberculosis chemotherapy,idiopathic thrombocytopenic purpura in adults, secondarythrombocytopenia in adults, acquired (autoimmune) hemolytic anemia,leukemias and lymphomas in adults, acute leukemia of childhood,ulcerative colitis, regional enteritis, Crohn's disease, Sjogren'ssyndrome, autoimmune vasculitis, multiple sclerosis, myasthenia gravis,sepsis and chronic obstructive pulmonary disease.

Also preferred are methods for preventing or inhibiting the onset of ortreating a disease associated with AP-1 and/or NFκB inducedtranscription comprising administering to a patient in need of treatmenta therapeutically effective amount of at least one compound havingformulae (I) (II) or (II) as described above.

Also preferred are methods for preventing or inhibiting the onset of ortreating a disease associated with AP-1 and/or NFκB dependent geneexpression, that is a disease associated with the expression of a geneunder the regulatory control of AP-1 and/or NFκB comprisingadministering to a patient in need of treatment a therapeuticallyeffective amount of at least one compound having formulae (I) (II) or(III) as described above.

Methods of Preparation

The compounds of the present invention may be synthesized by manymethods available to those skilled in the art of organic chemistry. Ageneral synthetic scheme for preparing compounds of the presentinvention is described below. The scheme is illustrative and is notmeant to limit the possible techniques one skilled in the art may use toprepare the compounds disclosed herein. Different methods to prepare thecompounds of the present invention will be evident to those skilled inthe art. Additionally, the various steps in the synthesis may beperformed in an alternate sequence in order to give the desired compoundor compounds. Examples of compounds of the present invention prepared bymethods described in Scheme I are given below.

The intermediate triazol-1-yl-ketones (c) are prepared by brominatingthe appropriately substituted ketone (a) with bromine in dioxane. Thebrominated ketone (b) is then stirred with 1,2,4-triazole and K₂CO₃ inacetonitrile to afford the triazol-1-yl ethanones (c). Titanium chlorideand sodium cyanoborohydride are then used to effect the reductivecoupling of (c) and the desired amine to give the final product (d).

Definition of Terms

The following are definitions of terms used in this specification andappended claims. The initial definition provided for a group or termherein applies to that group or term throughout the specification andclaims, individually or as part of another group, unless otherwiseindicated.

The term “alkyl” refers to straight or branched chain hydrocarbon groupshaving 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. Lower alkylgroups, that is, alkyl groups of 1 to 4 carbon atoms, are mostpreferred. When numbers appear in a subscript after the symbol “C”, thesubscript defines with more specificity the number of carbon atoms thata particular group may contain. For example, “C₁₋₆alkyl” refers tostraight and branched chain alkyl groups with one to six carbon atoms,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl,and so forth.

The term “substituted alkyl” refers to an alkyl group as defined abovehaving one, two, or three substituents selected from the groupconsisting of halo (e.g., trifluoromethyl), alkenyl, alkynyl, nitro,cyano, amino, oxo(═O), hydroxy, alkoxy, alkylthio, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, —NHSO₂, —N(alkyl)SO₂, —NHSO₂(alkyl),—NHSO₂(aryl), —N(alkyl)SO₂(alkyl), —N(alkyl)SO₂(aryl), —SO₂(alkyl),—SO₂(aryl), —SO₂N(aryl)(alkyl), —SO₂N(alkyl)₂, —CO₂H, —C(═O)H,—CO₂-alkyl, —C(═O)alkyl, —C(═O)aryl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)NH(cycloalkyl), —C(═O)N(alkyl)₂, —NH—CH₂—CO₂H—NH—CH(alkyl)-CO₂H,—NH—CH₂—CO₂-alkyl, —NH—CH(alkyl)-CO₂-alkyl, ═N—OH, ═N—O-alkyl, aryl,heteroaryl, heterocyclo, cycloalkyl, and substituted cycloalkyl,including phenyl, benzyl, phenylethyl, phenyloxy, and phenylthio. When asubstituted alkyl includes an aryl, heterocyclo, or heteroarylsubstituent, said ringed systems are as defined below and thus may havezero, one, two, or three substituents, also as defined below.

When the term “alkyl” is used together with another group, such as in“arylalkyl”, this conjunction defines with more specificity at least oneof the substituents that the substituted alkyl will contain. Forexample, “arylalkyl” refers to a substituted alkyl group as definedabove where one of the substituents is aryl, such as benzyl.

The term heteroalkyl refers to straight or branched chain hydrocarbongroups, having single or double bonds, or combinations thereof, in whichone or more skeletal atoms is oxygen, nitrogen, sulfur, or combinationsthereof.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms and at least one double bond. Alkenylgroups of 2 to 6 carbon atoms and having one double bond are preferred.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms and at least one triple bond. Alkynylgroups of 2 to 6 carbon atoms and having one triple bond are mostpreferred.

The term “alkoxy” refers to an alkyl or substituted alkyl group asdefined above having one, two or three oxygen atoms (—O—) in the alkylchain. For example, the term “alkoxy” includes the groups —O—C₁₋₁₂alkyl,—C₁₋₆alkylene-O—C₁₋₆alkyl, —C₁₋₄alkylene-O—C₁₋₄alkylene-O—C₁₋₄alkyl,O—C₁₋₄alkylene-O—C₁₋₄alkylene-O—C₁₋₄alkyl, and so forth.

The term “thioalkyl” or “alkylthio” refers to an alkyl or substitutedalkyl group as defined above bonded through one or more sulfur (—S—)atoms. For example, the term “thioalkyl” or “alkylthio” includes thegroups —S—C₁₋₁₂alkyl, —S—C₁₋₆alkylene-S—C₁₋₆alkyl, etc.

The term “aminoalkyl” refers to an alkyl or substituted alkyl group asdefined above bonded through one or more nitrogen (—NR—) atoms. Forexample, the term “aminoalkyl” includes the groups —NR—C₁₋₁₂alkyl,—NR—C₁₋₆alkylene-NR—C₁₋₆alkyl, etc. (where R is preferably hydrogen butmay include alkyl or substituted alkyl as defined above.) When asubscript is used with reference to an alkoxy, thioalkyl or aminoalkyl,the subscript refers to the number of carbon atoms that the group maycontain in addition to heteroatoms. Thus, for example, monovalentC₁₋₂aminoalkyl includes the groups —CH₂—NH₂, —NH—CH₃, —(CH₂)₂—NH₂,—NH—CH₂—CH₃, —CH₂—NH₂—CH₃, and —N—(CH₂)₂. A lower aminoalkyl comprisesan aminoalkyl having one to four carbon atoms. “Amino” refers to thegroup NH₂.

The alkoxy, thioalkyl, or aminoalkyl groups may be monovalent orbivalent. By “monovalent” it is meant that the group has a valency(i.e., power to combine with another group), of one, and by “bivalent”it is meant that the group has a valency of two. Thus, for example, amonovalent alkoxy includes groups such as —O—C₁₋₁₂alkyl,—C₁₋₆alkylene-O—C₁₋₆alkyl, —C₁₋₄alkylene-O—C₁₋₄alkylene-O—C₁₋₄alkyl,whereas a bivalent alkoxy includes groups such as —O—C₁₋₁₂alkylene-,—C₁₋₆alkylene-O—C₁₋₆alkylene-,—C₁₋₄alkylene-O—C₁₋₄alkylene-O—C₁₋₄alkylene-, and so forth.

The term “acyl” refers to a carbonyl group

linked to an organic radical including an alkyl, alkenyl, alkynyl,aminoalkyl, substituted alkyl, substituted alkenyl, or substitutedalkynyl, as defined above. The organic radical to which the carbonylgroup is attached may be monovalent (e.g., —C(═O)-alkyl), or bivalent(e.g., —C(═O)alkylene, etc.)

The term “alkoxycarbonyl” refers to a carboxy or ester group

linked to an organic radical including an alkyl, alkenyl, alkynyl,aminoalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl,or substituted aminoalkyl group, as defined above. The organic radicalto which the carboxy group is attached may be monovalent (e.g.,—CO₂-alkyl), or bivalent (e.g., —CO₂-alkylene, etc.)

The term “sulfonyl” refers to a sulphoxide group (i.e., —S(O)₁₋₂—)linked to an organic radical including an alkyl, alkenyl, alkynyl,aminoalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl,or substituted aminoalkyl group, as defined above. The organic radicalto which the sulphoxide group is attached may be monovalent (e.g.,—SO₂-alkyl), or bivalent (e.g., —SO₂-alkylene, etc.)

The term “sulfonamide” refers to the group —S(O)₂NR_(a)R_(b), whereinR_(a) and R_(b) may be hydrogen or alkyl, alkenyl, alkynyl, aminoalkyl,substituted alkyl, substituted alkenyl, substituted alkynyl, orsubstituted aminoalkyl group, as defined above. R_(a) and R_(b) may bemonovalent or bivalent (e.g., —SO₂—NH-alkylene, etc.)

The term “cycloalkyl” refers to fully saturated and partiallyunsaturated hydrocarbon rings of 3 to 9, preferably 3 to 7 carbon atoms.The term “cycloalkyl” includes such rings having zero, one, two, orthree substituents selected from the group consisting of halo, alkyl,substituted alkyl (e.g., trifluoromethyl), alkenyl, alkynyl, nitro,cyano, amino, oxo, hydroxy, alkoxy, alkylthio, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, —NHSO₂, —N(alkyl)SO₂, —NHSO₂(alkyl),—NHSO₂(aryl), —N(alkyl)SO₂(alkyl), —N(alkyl)SO₂(aryl), —SO₂(alkyl),—SO₂(aryl), —SO₂N(aryl)(alkyl), —SO₂N(alkyl)₂, —CO₂H, —C(═O)H,CO₂-alkyl, —C(═O)alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)NH(cycloalkyl), —C(═O)N(alkyl)₂, —NH—CH₂—CO₂H, —NH—CH(alkyl)-CO₂H,—NH—CH₂—CO₂-alkyl, —NH—CH(alkyl)-CO₂-alkyl, ═N—OH, ═N—O-alkyl, aryl,heteroaryl, heterocyclo, and a five or six membered ketal, e.g.,1,3-dioxolane or 1,3-dioxane.

The term “halo” or “halogen” refers to chloro, bromo, fluoro and iodo.

The term “haloalkyl” means a substituted alkyl having one or more halosubstituents. For example, “haloalkyl” includes mono, bi, andtrifluoromethyl.

The term “haloalkoxy” means an alkoxy group having one or more halosubstituents. For example, “haloalkoxy” includes OCF₃.

The term “aryl” refers to phenyl, biphenyl, 1-naphthyl and 2-naphthyl,with phenyl being preferred. The term “aryl” includes such rings havingzero, one, two or three substituents selected from the group consistingof halo, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano,amino, hydroxy, alkoxy, alkylthio, —NH(alkyl), —NH(cycloalkyl),—N(alkyl)₂, —NHSO₂, —N(alkyl)SO₂, —NHSO₂(alkyl), —NHSO₂(aryl),—N(alkyl)SO₂(alkyl), —N(alkyl)SO₂(aryl), —SO₂(alkyl), —SO₂(aryl),—SO₂N(aryl)(alkyl), —SO₂N(alkyl)₂, —CO₂H, —C(═O)H, CO₂-alkyl,—C(═O)alkyl, —C(═O)NH₂, —C(═O)NH(alkyl), —C(═O)NH(cycloalkyl),—C(═O)N(alkyl)₂, —NH—CH₂—CO₂H, —NH—CH(alkyl)-CO₂H, —NH—CH₂—CO₂-alkyl,—NH—CH(alkyl)-CO₂-alkyl, phenyl, benzyl, napthyl, phenylethyl,phenyloxy, phenylthio, cycloalkyl, substituted cycloalkyl, heterocyclo,and heteroaryl. Addtionally, when reference is made herein tooptionally-substituted aryl groups as selections for R¹, R^(4a) R^(4b)and R^(4c), such aryl groups may in addition to the foregoingsubstituents contain one or more substituents selected from OR^(c),NR^(c)R^(d), CO₂R^(c), C(═O)R^(c), C(═O)NR^(c)R^(d), NR^(c)C(═O)R^(d),NR^(c)C(═O)OR^(d), S(O)₀₋₂R^(c), NR^(c)SO₂R^(d), SO₂NR^(c)R^(d),—NHCH(alkyl)CO₂R^(c), wherein R^(c) and R^(d) are (i) selectedindependently of each other are hydrogen, alkyl, substituted alkyl,substituted alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, orheterocyclo; or (ii) taken together form a heterocyclo which in turn maybe optionally substituted as set forth below.

The term “heterocyclo” refers to substituted and unsubstitutednon-aromatic 3 to 7 membered monocyclic groups, 7 to 11 memberedbicyclic groups, and 10 to 15 membered tricyclic groups, in which atleast one of the rings has at least one heteroatom (O, S or N). Eachring of the heterocyclo group containing a heteroatom can contain one ortwo oxygen or sulfur atoms and/or from one to four nitrogen atomsprovided that the total number of heteroatoms in each ring is four orless, and further provided that the ring contains at least one carbonatom. The fused rings completing bicyclic and tricyclic groups maycontain only carbon atoms and may be saturated, partially saturated, orunsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quaternized. The heterocyclogroup may be attached at any available nitrogen or carbon atom. Theheterocyclo ring may contain zero, one, two or three substituentsselected from the group consisting of halo, alkyl, substituted alkyl,alkenyl, alkynyl, nitro, cyano, amino, oxo, hydroxy, alkoxy, alkylthio,—NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, —NHSO₂, —N(alkyl)SO₂,—NHSO₂(alkyl), —NHSO₂(aryl), —N(alkyl)SO₂(alkyl), —N(alkyl)SO₂(aryl),—SO₂(alkyl), —SO₂(aryl), —SO₂N(aryl)(alkyl), —SO₂N(alkyl)₂, —CO₂H,—C(═O)H, CO₂-alkyl, —C(═O)alkyl, —C(═O)aryl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)NH(cycloalkyl), —C(═O)N(alkyl)₂, —NH—CH₂—CO₂H, —NH—CH₂—CO₂-alkyl,—NHCH(C₁₋₄alkyl)-CO₂H, —NHCH(C₁₋₄alkyl)CO₂-alkyl, aryl, heteroaryl,heterocyclo, ═N—OH, ═N—O-alkyl, and a five or six membered ketal, e.g.,1,3-dioxolane or 1,3-dioxane.

Exemplary monocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl,imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like. Exemplarybicyclic heterocyclo groups include quinuclidinyl.

The term “heteroaryl” refers to substituted and unsubstituted aromatic 5or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and11 to 14 membered tricyclic groups which have at least one heteroatom(O, S or N) in at least one of the rings. Each ring of the heteroarylgroup containing a heteroatom can contain one or two oxygen or sulfuratoms and/or from one to four nitrogen atoms provided that the totalnumber of heteroatoms in each ring is four or less and each ring has atleast one carbon atom. The fused rings completing the bicyclic andtricyclic groups may contain only carbon atoms and may be saturated,partially saturated, or unsaturated. The nitrogen and sulfur atoms mayoptionally be oxidized and the nitrogen atoms may optionally bequaternized. Heteroaryl groups which are bicyclic or tricyclic mustinclude at least one fully aromatic ring but the other fused ring orrings may be aromatic or non-aromatic. The heteroaryl group may beattached at any available nitrogen or carbon atom of any ring.

The heteroaryl ring system may contain zero, one, two or threesubstituents selected from the group consisting of halo, alkyl,substituted alkyl, alkenyl, alkynyl, nitro, cyano, amino, hydroxy,alkoxy, alkylthio, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, —NHSO₂,—N(alkyl)SO₂, —NHSO₂(alkyl), —NHSO₂(aryl), —N(alkyl)SO₂(alkyl),—N(alkyl)SO₂(aryl), —SO₂(alkyl), —SO₂(aryl), —SO₂N(aryl)(alkyl),—SO₂N(alkyl)₂, —CO₂H, —C(═O)H, CO₂-alkyl, —C(═O)alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)NH(cycloalkyl), —C(═O)N(alkyl)₂, —NH—CH₂—CO₂H,—NH—CH(alkyl)-CO₂H, —NH—CH₂—CO₂-alkyl, —NH—CH(alkyl)-CO₂-alkyl, phenyl,benzyl, phenylethyl, phenyloxy, phenylthio, cycloalkyl, substitutedcycloalkyl, heterocyclo, and heteroaryl. Addtionally, when reference ismade herein to optionally-substituted heteroaryl groups as selectionsfor R¹, R^(4a) R^(4b) and R⁴, such heteroaryl groups may in addition tothe foregoing substituents contain one or more substituents selectedfrom OR^(c), NR^(c)R^(d), CO₂R^(c), C(═O)R^(c), C(═O)NR^(c)R^(d),NR^(c)C(═O)R^(d), NR^(c)C(═O)OR^(d), S(O)₀₋₂R^(c), NR^(c)SO₂R^(d),SO₂NR^(c)R^(d), —NHCH(alkyl)CO₂R^(c), wherein R^(c) and R^(d) are (i)selected independently of each other are hydrogen, alkyl, substitutedalkyl, substituted alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, orheterocyclo; or (ii) taken together form a heterocyclo which in turn maybe optionally substituted as set forth below.

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl,dihydroisoindolyl, tetrahydroquinolinyl and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.One example of a benzindolyl group is benz[c,d]indole which has thefollowing structure

The term “optionally substituted” is intended to be synonymous withsubstituted or unsubstituted.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds.

Compounds of formula (I) include salts, prodrugs and solvates. The term“salt(s)” denotes acidic and/or basic salts formed with inorganic and/ororganic acids and bases. In addition, the term “salt(s) may includezwitterions (inner salts), e.g., when a compound of formula (I) containsboth a basic moiety, such as an amine or a pyridine or imidazole ring,and an acidic moiety, such as a carboxylic acid. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, such as, for example, acceptable metal and amine salts inwhich the cation does not contribute significantly to the toxicity orbiological activity of the salt. However, other salts may be useful,e.g., in isolation or purification steps which may be employed duringpreparation, and thus, are contemplated within the scope of theinvention. Salts of the compounds of the formula (I) may be formed, forexample, by reacting a compound of the formula (I) with an amount ofacid or base, such as an equivalent amount, in a medium such as one inwhich the salt precipitates or in an aqueous medium followed bylyophilization.

Exemplary acid addition salts include acetates (such as those formedwith acetic acid or trihaloacetic acid, for example, trifluoroaceticacid), adipates, alginates, ascorbates, aspartates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts; alkaline earth metal salts such ascalcium and magnesium salts; barium, zinc, and aluminum salts; saltswith organic bases (for example, organic amines) such as trialkylaminessuch as triethylamine, procaine, dibenzylamine,N-benzyl-β-phenethylamine, 1-ephenamine, N,N′-dibenzylethylene-diamine,dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamineor similar pharmaceutically acceptable amines and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quaternized with agents such as lower alkyl halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others. Preferred salts includemonohydrochloride, hydrogensulfate, methanesulfonate, phosphate ornitrate.

Prodrugs and solvates of the inventive compounds are also contemplated.The term “prodrug” denotes a compound which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of the formula (I), and/or a salt and/orsolvate thereof. For example, compounds containing a carboxy group canform physiologically hydrolyzable esters which serve as prodrugs bybeing hydrolyzed in the body to yield formula (I) compounds per se. Suchprodrugs are preferably administered orally since hydrolysis in manyinstances occurs principally under the influence of the digestiveenzymes. Parenteral administration may be used where the ester per se isactive, or in those instances where hydrolysis occurs in the blood.Examples of physiologically hydrolyzable esters of compounds of formula(I) include C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g. acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl,C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g. methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

For further examples of such prodrug derivatives, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Acamedic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsenand H. Bundgaard, Chapter 5, “Design and Application of Prodrugs,” by H.Bundgaard, pp. 113-191 (1991); and

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992), each ofwhich is incorporated herein by reference.

Compounds of the formula (I), salts and prodrugs thereof may exist intheir tautomeric form, in which hydrogen atoms are transposed to otherparts of the molecules and the chemical bonds between the atoms of themolecules are consequently rearranged. It should be understood that theall tautomeric forms, insofar as they may exist, are included within theinvention. Additionally, inventive compounds may have trans and cisisomers and may contain one or more chiral centers, therefore existingin enantiomeric and diastereomeric forms. The invention includes allsuch isomers, as well as mixtures of cis and trans isomers, mixtures ofdiastereomers and racemic mixtures of enantiomers (optical isomers).When no specific mention is made of the configuration (cis, trans or Ror S) of a compound (or of an asymmetric carbon), then any one of theisomers or a mixture of more than one isomer is intended. The processesfor preparation can use racemates, enantiomers or diastereomers asstarting materials. When enantiomeric or diastereomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization. The inventive compoundsmay be in the free or hydrate form.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one or the R substituents.Consequently, compounds of formula (I) can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

Combinations

Where desired, the compounds of formula (I) may be used in combinationwith one or more other types of therapeutic agents such asimmunosuppressants, anticancer agents, anti-viral agents,anti-inflammatory agents, anti-fungal agents, antibiotics, anti-vascularhyperproliferation agents, anti-depressive agents, hypolipidemic agentsor lipid-lowering agents or lipid modulating agents, antidiabeticagents, anti-obesity agents, antihypertensive agents, plateletaggregation inhibitors, and/or anti-osteoporosis agents, which may beadministered orally in the same dosage form, in a separate oral dosageform or by injection.

The immunosuppressants which may be optionally employed in combinationwith compounds of formula (I) of the invention include cyclosporins, forexample cyclosporin A, mycophenolate, interferon-beta, deoxyspergolin,FK-506 or Ant.-IL-2.

The anti-cancer agents which may be optionally employed in combinationwith compounds of formula (I) of the invention include azathiprine,5-fluorouracil, cyclophosphamide, cisplatin, methotrexate, thiotepa,carboplatin, and the like.

The anti-viral agents which may be optionally employed in combinationwith compounds of formula (I) of the invention include abacavir,aciclovir, ganciclovir, zidanocin, vidarabine, and the like.

The anti-inflammatory agents which may be optionally employed incombination with compounds of formula (I) of the invention includenon-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, cox-2inhibitors such as celecoxib, rofecoxib, aspirin, naproxen, ketoprofen,diclofenac sodium, indomethacin, piroxicam, steroids such as prednisone,dexamethasone, hydrocortisone, triamcinolone diacetate, gold compounds,such as gold sodium thiomalate, TNF-α inhibitors such as tenidap,anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus orRapamune) or derivatives thereof, infliximab (Remicade® Centocor, Inc.).CTLA-4Ig, LEA29Y, antibodies such as anti-ICAM-3, anti-IL-2 receptor(Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4,anti-CD80, anti-CD86, monoclonal antibody OKT3, agents blocking theinteraction between CD40 and CD154 (a.k.a. “gp39”), such as antibodiesspecific for CD40 and/or CD154, fusion proteins such as etanercept,fusion proteins constructed from CD40 and/or CD154gp39 (e.g. CD40Ig andCD8gp39), inhibitors, such as nuclear translocation inhibitors, ofNF-kappa B function, such as deoxyspergualin (DSG).

The anti-fungal agents which may be optionally employed in combinationwith compounds of formula (I) of the invention include fluconazole,miconazole, amphotericin B, and the like.

The antibiotics which may be optionally employed in combination withcompounds of formula (I) of the invention include penicillin,tetracycline, amoxicillin, ampicillin, erythromycin, doxycycline,vancomycin, minocycline, clindamycin or cefalexin.

The anti-vascular hyperproliferation agents which may be optionallyemployed with compounds of formula (I) of the invention includemethotrexate, leflunomide, FK506 (tacrolimus, Prograf),

The hypolipidemic agent or lipid-lowering agent or lipid modulatingagents which may be optionally employed in combination with thecompounds of formula (1) of the invention may include 1, 2, 3 or moreMTP inhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, upregulators of LDL receptor activity, bileacid sequestrants, and/or nicotinic acid and derivatives thereof.

MTP inhibitors employed herein include MTP inhibitors disclosed in U.S.Pat. Nos. 5,595,872, 5,739,135, 5,712,279, 5,760,246, 5,827,875,5,885,983 and U.S. application Ser. No. 09/175,180 filed Oct. 20, 1998,now U.S. Pat. No. 5,962,440. Preferred are each of the preferred MTPinhibitors disclosed in each of the above patents and applications.

All of the above U.S. patents and applications are incorporated hereinby reference.

Most preferred MTP inhibitors to be employed in accordance with thepresent invention include preferred MTP inhibitors as set out in U.S.Pat. Nos. 5,739,135 and 5,712,279, and 5,760,246.

The most preferred MTP inhibitor is9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

The hypolipidemic agent may be an HMG CoA reductase inhibitor whichincludes, but is not limited to, mevastatin and related compounds asdisclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and relatedcompounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin andrelated compounds such as disclosed in U.S. Pat. No. 4,346,227,simvastatin and related compounds as disclosed in U.S. Pat. Nos.4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may beemployed herein include, but are not limited to, fluvastatin, disclosedin U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos.5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos.4,681,893, 5,273,995, 5,385,929 and 5,686,104, itavastatin(Nissan/Sankyo's nisvastatin (NK-104)) disclosed in U.S. Pat. No.5,011,930, Shionogi-Astra/Zeneca visastatin (ZD-4522) disclosed in U.S.Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat.No. 5,753,675, pyrazole analogs of mevalonolactone derivatives asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No. 0,142,146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

In addition, phosphinic acid compounds useful in inhibiting HMG CoAreductase suitable for use herein are disclosed in GB 2205837.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller et al, J. Med. Chem., V. 31, No.10, 1869-1871 (1988) including isoprenoid(phosphinyl-methyl)phosphonates as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., et al., CurrentPharmaceutical Design, 2, 1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 20, 243-249 (1977), the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 98, 1291-1293 (1976),phosphinylphosphonates reported by McClard, R. W., et al., J.A.C.S.,109, 5544 (1987), and cyclopropanes reported by Capson, T. L., PhDdissertation, Dept. Med. Chem. U of Utah, Abstract, Table of Contents,pp 16, 17, 40-43, 48-51, Summary, (June 1987).

Other hypolipidemic agents suitable for use herein include, but are notlimited to, fibric acid derivatives, such as fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like,probucol, and related compounds as disclosed in U.S. Pat. No. 3,674,836,probucol and gemfibrozil being preferred, bile acid sequestrants such ascholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®)and cholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc),Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil(HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine(SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814(azulene derivative), melinamide (Sumitomo), Sandoz 58-035, AmericanCyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives),nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylicacid, aspirin, poly(diallylmethylamine) derivatives such as disclosed inU.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammoniumchloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, andother known serum cholesterol lowering agents.

The hypolipidemic agent may be an ACAT inhibitor such as disclosed in,Drugs of the Future 24, 9-15 (Avasimibe, 1999); Nicolosi et al,Atherosclerosis, (1), 77-85 (1998); Ghiselli and Giancarlo, Cardiovasc.Drug Rev., 16(1), 16-30 (1998); Smith, C., et al, Bioorg. Med. Chem.Lett., 6(1), 47-50 (1996); Krause et al, Editor(s): Ruffolo, Robert R.,Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways, 173-98,(CRC, Boca Raton, Fla. 1995); Sliskovic et al, Curr. Med. Chem. 1(3),204-25 (1994); Stout et al, Chemtracts: Org. Chem., 8(6), 359-62,(1995); or TS-962 (Taisho Pharmaceutical Co. Ltd).

The hypolipidemic agent may be an upregulator of LD2 receptor activitysuch as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's ezetimibe (SCH58235) and SCH48461 as wellas those disclosed in Atherosclerosis, 115, 45-63 (1995) and J. Med.Chem., 41, 973 (1998).

The hypolipidemic agent may be an ileal Na⁺/bile acid cotransporterinhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).

The lipid-modulating agent may be a cholesteryl ester transfer protein(CETP) inhibitor such as Pfizer's CP 529,414 (WO/0038722 and EP 818448)and Pharmacia's SC-744 and SC-795.

The ATP citrate lyase inhibitor which may be employed in the combinationof the invention may include, for example, those disclosed in U.S. Pat.No. 5,447,954.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, itavastatin and visastatin andZD-4522.

The above-mentioned U.S. patents are incorporated herein by reference.The amounts and dosages employed will be as indicated in the Physician'sDesk Reference and/or in the patents set out above.

The compounds of formula (I) of the invention will be employed in aweight ratio to the hypolipidemic agent (were present), within the rangefrom about 500:1 to about 1:500, preferably from about 100:1 to about1:100.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

The dosages and formulations for the hypolipidemic agent will be asdisclosed in the various patents and applications discussed above.

The dosages and formulations for the other hypolipidemic agent to beemployed, where applicable, will be as set out in the latest edition ofthe Physicians' Desk Reference.

For oral administration, a satisfactory result may be obtained employingthe MTP inhibitor in an amount within the range of from about 0.01 mg toabout 500 mg and preferably from about 0.1 mg to about 100 mg, one tofour times daily.

A preferred oral dosage form, such as tablets or capsules, will containthe MTP inhibitor in an amount of from about 1 to about 500 mg,preferably from about 2 to about 400 mg, and more preferably from about5 to about 250 mg, one to four times daily.

For oral administration, a satisfactory result may be obtained employingan HMG CoA reductase inhibitor, for example, pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin or cerivastatin in dosagesemployed as indicated in the Physician's Desk Reference, such as in anamount within the range of from about 1 to 2000 mg, and preferably fromabout 4 to about 200 mg.

The squalene synthetase inhibitor may be employed in dosages in anamount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

A preferred oral dosage form, such as tablets or capsules, will containthe HMG CoA reductase inhibitor in an amount from about 0.1 to about 100mg, preferably from about 0.5 to about 80 mg, and more preferably fromabout 1 to about 40 mg.

A preferred oral dosage form, such as tablets or capsules will containthe squalene synthetase inhibitor in an amount of from about 10 to about500 mg, preferably from about 25 to about 200 mg.

The hypolipidemic agent may also be a lipoxygenase inhibitor including a15-lipoxygenase (15-LO) inhibitor such as benzimidazole derivatives asdisclosed in WO 97/12615, 15-LO inhibitors as disclosed in WO 97/12613,isothiazolones as disclosed in WO 96/38144, and 15-LO inhibitors asdisclosed by Sendobry et al., Brit. J. Pharmacology 120, 1199-1206(1997), and Cornicelli et al., Current Pharmaceutical Design, 5, 11-20(1999).

The compounds of formula (I) and the hypolipidemic agent may be employedtogether in the same oral dosage form or in separate oral dosage formstaken at the same time.

The compositions described above may be administered in the dosage formsas described above in single or divided doses of one to four timesdaily. It may be advisable to start a patient on a low dose combinationand work up gradually to a high dose combination.

The preferred hypolipidemic agent is pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin or cerivastatin as well as niacinand/or cholestagel.

The other antidiabetic agent which may be optionally employed incombination with the compound of formula (I) may be 1, 2, 3 or moreantidiabetic agents or antihyperglycemic agents including insulinsecretagogues or insulin sensitizers, or other antidiabetic agentspreferably having a mechanism of action different from the compounds offormula (I) of the invention, which may include biguanides, sulfonylureas, glucosidase inhibitors, PPAR γ agonists, such asthiazolidinediones, aP2 inhibitors, dipeptidyl peptidase IV (DP4)inhibitors, SGLT2 inhibitors, and/or meglitinides, as well as insulin,and/or glucagon-like peptide-1 (GLP-1).

The other antidiabetic agent may be an oral antihyperglycemic agentpreferably a biguanide such as metformin or phenformin or salts thereof,preferably metformin HCl.

Where the antidiabetic agent is a biguanide, the compounds of formula(I) will be employed in a weight ratio to biguanide within the rangefrom about 0.001:1 to about 10:1, preferably from about 0.01:1 to about5:1.

The other antidiabetic agent may also preferably be a sulfonyl urea suchas glyburide (also known as glibenclamide), glimepiride (disclosed inU.S. Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, otherknown sulfonylureas or other antihyperglycemic agents which act on theATP-dependent channel of the □-cells, with glyburide and glipizide beingpreferred, which may be administered in the same or in separate oraldosage forms.

The compounds of formula (I) will be employed in a weight ratio to thesulfonyl urea in the range from about 0.01:1 to about 100:1, preferablyfrom about 0.02:1 to about 5:1.

The oral antidiabetic agent may also be a glucosidase inhibitor such asacarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol (disclosedin U.S. Pat. No. 4,639,436), which may be administered in the same or ina separate oral dosage forms.

The compounds of formula (I) will be employed in a weight ratio to theglucosidase inhibitor within the range from about 0.01:1 to about 100:1,preferably from about 0.05:1 to about 10:1.

The compounds of formula (I) may be employed in combination with a PPARγ agonist such as a thiazolidinedione oral anti-diabetic agent or otherinsulin sensitizers (which has an insulin sensitivity effect in NIDDMpatients) such as troglitazone (Warner-Lambert's Rezulin®, disclosed inU.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone (Takeda),Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone andpioglitazone.

The compounds of formula (I) will be employed in a weight ratio to thethiazolidinedione in an amount within the range from about 0.01:1 toabout 100:1, preferably from about 0.05 to about 10:1.

The sulfonyl urea and thiazolidinedione in amounts of less than about150 mg oral antidiabetic agent may be incorporated in a single tabletwith the compounds of formula (I).

The compounds of formula (I) may also be employed in combination with aantihyperglycemic agent such as insulin or with glucagon-like peptide-1(GLP-1) such as GLP-1(1-36)amide, GLP-1(7-36)amide, GLP-1(7-37) (asdisclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of whichis incorporated herein by reference), as well as AC2993 (Amylin) andLY-315902 (Lilly), which may be administered via injection, intranasal,inhalation or by transdermal or buccal devices.

Where present, metformin, the sulfonyl ureas, such as glyburide,glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and theglucosidase inhibitors acarbose or miglitol or insulin (injectable,pulmonary, buccal, or oral) may be employed in formulations as describedabove and in amounts and dosing as indicated in the Physician's DeskReference (PDR).

Where present, metformin or salt thereof may be employed in amountswithin the range from about 500 to about 2000 mg per day which may beadministered in single or divided doses one to four times daily.

Where present, the thiazolidinedione anti-diabetic agent may be employedin amounts within the range from about 0.01 to about 2000 mg/day whichmay be administered in single or divided doses one to four times perday.

Where present insulin may be employed in formulations, amounts anddosing as indicated by the Physician's Desk Reference.

Where present GLP-1 peptides may be administered in oral buccalformulations, by nasal administration or parenterally as described inU.S. Pat. No. 5,346,701 (TheraTech), U.S. Pat. Nos. 5,614,492 and5,631,224 which are incorporated herein by reference.

The other antidiabetic agent may also be a PPAR α/γ dual agonist such asAR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (KyorinMerck) as well as those disclosed by Murakami et al., Diabetes, 47,1841-1847 (1998).

The antidiabetic agent may be an SGLT2 inhibitor such as disclosed inU.S. application Ser. No. 09/679,027, filed Oct. 4, 2000 employingdosages as set out therein. Preferred are the compounds designated aspreferred in the above application.

The antidiabetic agent may be an aP2 inhibitor such as disclosed in U.S.application Ser. No. 09/391,053, filed Sep. 7, 1999, and in U.S.application Ser. No. 09/519,079, filed Mar. 6, 2000 employing dosages asset out herein. Preferred are the compounds designated as preferred inthe above application.

The antidiabetic agent may be a DP4 inhibitor such as disclosed in U.S.application Ser. No. 09/788,173 filed Feb. 16, 2001, WO99/38501,WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431(PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) (preferred) as disclosed by Hughes et al, Biochemistry,38(36), 11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540,2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996) employing dosages as set out in the above references.

The meglitinide which may optionally be employed in combination with thecompound of formula (I) of the invention may be repaglinide, nateglinide(Novartis) or KAD1229 (PF/Kissei), with repaglinide being preferred.

The compound of formula (I) will be employed in a weight ratio to themeglitinide, PPAR γ agonist, PPAR α/γ dual agonist, aP2 inhibitor, DP4inhibitor or SGLT2 inhibitor within the range from about 0.01:1 to about100:1, preferably from about 0.05 to about 10:1.

The other type of therapeutic agent which may be optionally employedwith a compound of formula (I) may be 1, 2, 3 or more of an anti-obesityagent including a beta 3 adrenergic agonist, a lipase inhibitor, aserotonin (and dopamine) reuptake inhibitor, an aP2 inhibitor, a thyroidreceptor agonist and/or an anorectic agent.

The beta 3 adrenergic agonist which may be optionally employed incombination with a compound of formula (I) may be AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615,5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648being preferred.

The lipase inhibitor which may be optionally employed in combinationwith a compound of formula (I) may be orlistat or ATL-962 (Alizyme),with orlistat being preferred.

The serotonin (and dopoamine) reuptake inhibitor which may be optionallyemployed in combination with a compound of formula (1) may besibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), withsibutramine and topiramate being preferred.

The thyroid receptor agonist which may be optionally employed incombination with a compound of formula (I) may be a thyroid receptorligand as disclosed in WO97/21993 (U. Cal SF), WO99/00353 (KaroBio),GB98/284425 (KaroBio), and U.S. Provisional Application 60/183,223 filedFeb. 17, 2000, with compounds of the KaroBio applications and the aboveU.S. provisional application being preferred.

The anorectic agent which may be optionally employed in combination witha compound of formula (I) may be dexamphetamine, phentermine,phenylpropanolamine or mazindol, with dexamphetamine being preferred.

The various anti-obesity agents described above may be employed in thesame dosage form with the compound of formula (I) or in different dosageforms, in dosages and regimens as generally known in the art or in thePDR.

The antihypertensive agents which may be employed in combination withthe compound of formula (I) of the invention include ACE inhibitors,angiotensin II receptor antagonists, NEP/ACE inhibitors, as well ascalcium channel blockers, β-adrenergic blockers and other types ofantihypertensive agents including diuretics.

The angiotensin converting enzyme inhibitor which may be employed hereinincludes those containing a mercapto (—S—) moiety such as substitutedproline derivatives, such as any of those disclosed in U.S. Pat. No.4,046,889 to Ondetti et al. mentioned above, with captopril, that is,1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, being preferred, andmercaptoacyl derivatives of substituted prolines such as any of thosedisclosed in U.S. Pat. No. 4,316,906 with zofenopril being preferred.

Other examples of mercapto containing ACE inhibitors that may beemployed herein include rentiapril (fentiapril, Santen) disclosed inClin. Exp. Pharmacol. Physiol. 10:131 (1983); as well as pivopril andYS980.

Other examples of angiotensin converting enzyme inhibitors which may beemployed herein include any of those disclosed in U.S. Pat. No.4,374,829 mentioned above, withN-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline, that is,enalapril, being preferred, any of the phosphonate substituted amino orimino acids or salts disclosed in U.S. Pat. No. 4,452,790 with(S)-1-[6-amino-2-[[hydroxy-(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L-prolineor (ceronapril) being preferred, phosphinylalkanoyl prolines disclosedin U.S. Pat. No. 4,168,267 mentioned above with fosinopril beingpreferred, any of the phosphinylalkanoyl substituted prolines disclosedin U.S. Pat. No. 4,337,201, and the phosphonamidates disclosed in U.S.Pat. No. 4,432,971 discussed above.

Other examples of ACE inhibitors that may be employed herein includeBeecham's BRL 36,378 as disclosed in European Patent Application Nos.80822 and 60668; Chugai's MC-838 disclosed in C.A. 102:72588v and Jap.J. Pharmacol. 40:373 (1986); Ciba-Geigy's CGS 14824(3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1-(3S)-benzazepine-1acetic acid HCl) disclosed in U.K. Patent No. 2103614 and CGS 16,617(3(S)-[[(1S)-5-amino-1-carboxypentyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-ethanoicacid) disclosed in U.S. Pat. No. 4,473,575; cetapril (alacepril,Dainippon) disclosed in Eur. Therap. Res. 39:671 (1986); 40:543 (1986);ramipril (Hoechsst) disclosed in Euro. Patent No. 79-022 and Curr. Ther.Res. 40:74 (1986); Ru 44570 (Hoechst) disclosed in Arzneimittelforschung34:1254 (1985), cilazapril (Hoffman-LaRoche) disclosed in J. Cardiovasc.Pharmacol. 9:39 (1987); R 31-2201 (Hoffman-LaRoche) disclosed in FEBSLett. 165:201 (1984); lisinopril (Merck), indalapril (delapril)disclosed in U.S. Pat. No. 4,385,051; indolapril (Schering) disclosed inJ. Cardiovasc. Pharmacol. 5:643, 655 (1983), spirapril (Schering)disclosed in Acta. Pharmacol. Toxicol. 59 (Supp. 5):173 (1986);perindopril (Servier) disclosed in Eur. J. clin. Pharmacol. 31:519(1987); quinapril (Warner-Lambert) disclosed in U.S. Pat. No. 4,344,949and CI925 (Warner-Lambert)([3S-[2[R(*)R(*)]]3R(*)]-2-[2-[[1-(ethoxy-carbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylicacid HCl)disclosed in Pharmacologist 26:243, 266 (1984), WY-44221(Wyeth) disclosed in J. Med. Chem. 26:394 (1983).

Preferred ACE inhibitors are captopril, fosinopril, enalapril,lisinopril, quinapril, benazepril, fentiapril, ramipril and moexipril.

NEP/ACE inhibitors may also be employed herein in that they possessneutral endopeptidase (NEP) inhibitory activity and angiotensinconverting enzyme (ACE) inhibitory activity. Examples of NEP/ACEinhibitors suitable for use herein include those disclosed in U.S. Pat.Nos. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516, 4,749,688,5,552,397, 5,504,080, 5,612,359, 5,525,723, European Patent Application0599,444, 0481,522, 0599,444, 0595,610, European Patent Application0534363A2, 534,396 and 534,492, and European Patent Application0629627A2.

Preferred are those NEP/ACE inhibitors and dosages thereof which aredesignated as preferred in the above patents/applications which U.S.patents are incorporated herein by reference; most preferred areomapatrilat, BMS 189,921([S—(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat)) and CGS 30440.

The angiotensin II receptor antagonist (also referred to herein asangiotensin II antagonist or AII antagonist) suitable for use hereinincludes, but is not limited to, irbesartan, losartan, valsartan,candesartan, telmisartan, tasosartan or eprosartan, with irbesartan,losartan or valsartan being preferred.

A preferred oral dosage form, such as tablets or capsules, will containthe ACE inhibitor or AII antagonist in an amount within the range fromabut 0.1 to about 500 mg, preferably from about 5 to about 200 mg andmore preferably from about 10 to about 150 mg.

For parenteral administration, the ACE inhibitor, angiotensin IIantagonist or NEP/ACE inhibitor will be employed in an amount within therange from about 0.005 mg/kg to about 10 mg/kg and preferably from about0.01 mg/kg to about 1 mg/kg.

Where a drug is to be administered intravenously, it will be formulatedin conventional vehicles, such as distilled water, saline, Ringer'ssolution or other conventional carriers.

It will be appreciated that preferred dosages of ACE inhibitor and AIIantagonist as well as other antihypertensives disclosed herein will beas set out in the latest edition of the Physician's Desk Reference(PDR).

Other examples of preferred antihypertensive agents suitable for useherein include omapatrilat (Vanlev®) amlodipine besylate (Norvasc®),prazosin HCl (Minipress®), verapamil, nifedipine, nadolol, diltiazem,felodipine, nisoldipine, isradipine, nicardipine, atenolol, carvedilol,sotalol, terazosin, doxazosin, propranolol, and clonidine HCl(Catapres®).

Diuretics which may be employed in combination with compounds of formula(I) include hydrochlorothiazide, torasemide, furosemide, spironolactono,and indapamide.

Antiplatelet agents which may be employed in combination with compoundsof formula (I) of the invention include aspirin, clopidogrel,ticlopidine, dipyridamole, abciximab, tirofiban, eptifibatide,anagrelide, and ifetroban, with clopidogrel and aspirin being preferred.

The antiplatelet drugs may be employed in amounts as indicated in thePDR. Ifetroban may be employed in amounts as set out in U.S. Pat. No.5,100,889.

Antiosteoporosis agents suitable for use herein in combination with thecompounds of formula (I) of the invention include parathyroid hormone orbisphosphonates, such as MK-217 (alendronate) (Fosamax®).

Dosages employed for the above drugs will be as set out in thePhysician's Desk Reference.

Pharmaceutical Formulations

The pharmaceutical composition of the invention includes apharmaceutically acceptable carrier, adjuvant or vehicle that may beadministered to a subject, together with a compound of the presentinvention, and which does not destroy the pharmacological activitythereof. Pharmaceutically acceptable carriers, adjuvants and vehiclesthat may be used in the pharmaceutical compositions of the presentinvention include, but are not limited to, the following: ionexchangers, alumina, aluminum stearate, lecithin, self-emulsifying drugdelivery systems (“SEDDS”) such as d(-tocopherol polyethyleneglycol 1000succinate), surfactants used in pharmaceutical dosage forms such asTweens or other similar polymeric delivery matrices, serum proteins suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β- and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives mayalso be used to enhance delivery of the modulators of the presentinvention.

The compositions of the present invention may contain other therapeuticagents as described below, and may be formulated, for example, byemploying conventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

The compounds of the invention may be administered by any suitablemeans, for example, orally, such as in the form of tablets, capsules,granules or powders; sublingually; buccally; parenterally, such as bysubcutaneous, intravenous, intramuscular, or intrasternal injection orinfusion techniques (e.g., as sterile injectable aqueous or non-aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; or rectally suchas in the form of suppositories; in dosage unit formulations containingnon-toxic, pharmaceutically acceptable vehicles or diluents. Thecompounds of the invention may, for example, be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved by the use of suitable pharmaceuticalcompositions including the compounds of the invention, or, particularlyin the case of extended release, by the use of devices such assubcutaneous implants or osmotic pumps. The compounds of the inventionmay also be administered liposomally.

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The present compounds may also be delivered through the oralcavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating thecompound(s) of the invention with fast dissolving diluents such asmannitol, lactose, sucrose and/or cyclodextrins. Also included in suchformulations may be high molecular weight excipients such as celluloses(Avicel) or polyethylene glycols (PEG). Such formulations may alsoinclude an excipient to aid mucosal adhesion such as hydroxy propylcellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), andagents to control release such as polyacrylic copolymer (e.g., Carbopol934). Lubricants, glidants, flavors, coloring agents and stabilizers mayalso be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid. The term “parenteral” as used hereinincludes subcutaneous, intracutaneous, intravenous, intramuscular,intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal,intralesional and intracranial injection or infusion techniques.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 0.1 to 500 mg/kg of bodyweight of active compound per day, or between 5 and 2000 mg per daywhich may be administered in a single dose or in the form of individualdivided doses, such as from 1 to 5 times per day. It will be understoodthat the specific dose level and frequency of dosage for any particularsubject may be varied and will depend upon a variety of factorsincluding the activity of the specific compound employed, the metabolicstability and length of action of that compound, the species, age, bodyweight, general health, sex and diet of the subject, the mode and timeof administration, rate of excretion, drug combination, and severity ofthe particular condition. Preferred subjects for treatment includeanimals, most preferably mammalian species such as humans, and domesticanimals such as dogs, cats and the like.

A typical capsule for oral administration contains compounds of formula(I) (250 mg), lactose (75 mg) and magnesium stearate (15 mg). Themixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250mg of compounds of formula (I) into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

The compounds of formula I of the invention are glucocorticoid receptormodulators as shown either by their ability to bind glucocorticoidreceptors in GR binding assays, or by their ability to inhibit AP-1activity as indicated in cellular transrespressional assays, and causenone to minimal transactivation as indicated in cellulartransscriptional assays.

The cellular transrespressional assay and cellular transcriptional assayemployed to determine activity are described in copending provisionalapplication No. 60/396,907, filed Jul. 18, 2002 which is incorporatedherein by reference. transactivation as indicated in cellulartransscriptional assays.

Glucocorticoid Receptor Binding Assay

In order to measure the binding of compounds to the glucocorticoidreceptor a commercially available kit was used (Glucocorticoid receptorcompetitor assay kit, Panvera Co., Madison, Wis.). Briefly, a celllysate containing the glucocorticoid receptor was mixed with afluorescently labeled glucocorticoid (dexamethasone) plus or minus testmolecule. After one hour at room temperature, the fluorescencepolarization (FP) of the samples were measured. The FP of a mixture ofreceptor, fluorescent probe (i.e. fluorescently labeled glucocorticoid)and 1 mM dexamethasone represented 100% competition, whereas, the FP ofthe mixture without dexamethasone was taken to be 100% binding. Thepercentage competition of test molecules were then compared to thesample with 1 mM dexamethasone and expressed as % relative bindingactivity with dexamethasone being 100% and no competition is 0%. Testmolecules were analyzed in the concentration range from 0.1 nM to 40 μM.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

The following abbreviations may be employed in the Examples:

-   H=hydrogen-   Ph=phenyl-   Bn=benzyl-   n-Pr=n-propyl-   t-Bu=tertiary butyl-   Me=methyl-   Et=ethyl-   TMS=trimethylsilyl-   TMSN₃=trimethylsilyl azide-   TBS=tert-butyldimethylsilyl-   FMOC=fluorenylmethoxycarbonyl-   Boc=tert-butoxycarbonyl-   Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl-   THF=tetrahydrofuran-   Et₂O=diethyl ether-   hex=hexanes-   EtOAc=ethyl acetate-   DMF=dimethyl formamide-   MeOH=methanol-   EtOH=ethanol-   i-PrOH=isopropanol-   DMSO=dimethyl sulfoxide-   DME=1,2 dimethoxyethane-   DCE=1,2 dichloroethane-   HMPA=hexamethyl phosphoric triamide-   HOAc or AcOH=acetic acid-   TFA=trifluoroacetic acid-   TFAA=trifluoroacetic anhydride-   i-Pr₂NEt=diisopropylethylamine-   Et₃N=triethylamine-   NMM=N-methyl morpholine-   DMAP=4-dimethylaminopyridine-   NaBH₄=sodium borohydride-   NaBH(OAc)₃=sodium triacetoxyborohydride-   DIBALH=diisobutyl aluminum hydride-   LAH or LiAlH₄=lithium aluminum hydride-   n-BuLi=n-butyllithium-   LDA=lithium diisopropylamide-   Pd/C=palladium on carbon-   PtO₂=platinum oxide-   KOH=potassium hydroxide-   NaOH=sodium hydroxide-   LiOH=lithium hydroxide-   K₂CO₃=potassium carbonate-   NaHCO₃=sodium bicarbonate-   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene-   EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or    EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or    1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)-   HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate-   HOAT=1-Hydroxy-7-azabenzotriazole-   BOP reagent=benzotriazol-1-yloxy-tris(dimethylamino)phosphonium    hexafluorophosphate-   NaN(TMS)₂=sodium hexamethyldisilazide or sodium    bis(trimethylsilyl)amide-   Ph₃P=triphenylphosphine-   Pd(OAc)₂=Palladium acetate-   (Ph₃P)₄Pd^(o)=tetrakis triphenylphosphine palladium-   TiCl₄=titanium (IV) chloride-   NaBH₃CN=sodium cyanoborohydride-   DEAD=diethyl azodicarboxylate-   DIAD=diisopropyl azodicarboxylate-   Cbz-Cl=benzyl chloroformate-   CAN=ceric ammonium nitrate-   SAX=Strong Anion Exchanger-   SCX=Strong Cation Exchanger-   Ar=argon-   N₂=nitrogen-   min=minute(s)-   h or hr=hour(s)-   L=liter-   mL=milliliter-   μL=microliter-   g=gram(s)-   mg=milligram(s)-   mol=moles-   mmol=millimole(s)-   meq=milliequivalent-   RT=room temperature-   sat or sat'd=saturated-   aq.=aqueous-   TLC=thin layer chromatography-   HPLC=high performance liquid chromatography-   LC/MS=high performance liquid chromatography/mass spectrometry-   MS or Mass Spec=mass spectrometry-   NMR=nuclear magnetic resonance-   NMR spectral data: s=singlet; d=doublet; m=multiplet; br=broad;    t=triplet-   mp=melting point

Materials

Reactions requiring air-sensitive manipulations were conducted under N₂atmosphere. Analytical TLC was performed on 0.20 mm silica gel 60 F254plates. Merck silica gel (60, particle size 0.040-0.063 mm) was used forflash column chromatography. NMR spectra were recorded on Varian Mercury300 MHz spectrometers. Chemical shifts (δ) were measured in parts permillion (ppm), and coupling constants (J values) are in Hz.High-resolution mass spectra (HR-MS) were recorded on a Micromass Q-TOFspectrometer. All chemicals were purchased from different commercialsources. Most of the reactions were carried out without optimization ofthe yield.

Representatives Synthetic Procedures Synthesis of the (1,2,4)-triazolylEthylamines

To a stirred solution of 2-chloro-1-(2,4-dichloro-phenyl)-ethanone (3.0g, 13.4 mmol) in 200 mL of CH₃CN, 1,2,4-triazole (1.39 g, 20.1 mmol) andK₂CO₃ (1.85 g, 13.4 mmol) was added. The solution was stirred at roomtemperature overnight. The solvent was removed and the residue wastreated with EtOAc and water. The organic layer was separated, driedover MgSO₄ and concentrated in vacuo. The crude product was purified viasilica gel chromatography (40-100% EtOAc/hexanes) to give 1.26 g (37%)of the pure ketone intermediate. 300 MHz ¹H NMR (CDCl₃) δ: 8.24 (s, 1H),8.20 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.51 (d, J=2.1 Hz, 1H), 7.39 (dd,J=8.4, 2.1 Hz, 1H), 5.62 (s, 2H); MS (m/e): 256.2.

To a solution of the ketone intermediate (0.05 mmol) and the desiredamine (0.10 mmol) in 1 mL 1,2-dichloroethane, TiCl₄ (0.15 mmol, 1Msolution in dichloromethane) and NaBH₃CN (0.10 mmol) were added. Themixture was heated to 85° C. for 16 h. After cooling to roomtemperature, the crude mixture was treated with with 1 mL water and 2 mLEt₂O. The ether layer was separated and dried in vacuo. The resultingsolid was purified via mass triggered RP-HPLC/MS.

The following compounds were synthesized with the appropriate startingmaterials using the conditions described above.

Exp. # A B R³ R⁴ Compound Structure 1

n-Pr H

2

Et H

4

n-Pr H

5

Et H

Et H

7

Et H

8

Et H

9

Et H

10

Me Me

11

Et H

12

n-Pr H

13

Et H

14

Me Me

15

Et H

16

Me H

17

Me Me

18

Me H

19

H H

1. A compound having formula (I),

including all stereoisomers thereof, wherein: A and B are independentlyaryl or heteroaryl, each of which is optionally substituted; R¹ is (i)hydrogen, COR⁹, CO₂R⁹, SO₂R⁹, S(O)R⁹, or CONR⁷R⁸; or (ii) C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆heteroalkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl, each group of which is optionally substituted; R², R³and R⁴ are independently hydrogen, C₁₋₆alkyl, C₁₋₆heteroalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, or heteroaryl, each group of which isoptionally substituted where valence allows; R⁵ and R⁶ are independently(i) hydrogen, F, Cl, Br, I, NO₂, CN, OR⁷, NR⁷R⁸, SR⁷, COR⁹, CO₂R⁹, orCONR⁷R⁸; or (ii) C₁₋₆alkyl, C₁₋₆heteroalkyl, C₃₋₈cycloalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, heteroarylalkyl, orarylalkyl, each group of which is optionally substituted; R⁷ and R⁸ areindependently at each occurence (i) hydrogen, COR⁹, SO₂R⁹, or S(O)R⁹; or(ii) C₁₋₆alkyl, C₁₋₆heteroalkyl C₁₋₆haloalkyl, aryl, heteroaryl,heteroarylalkyl, or arylalkyl, each group of which is optionallysubstituted; and R⁹ is, at each occurrence hydrogen, C₁₋₆alkyl,heteroalkyl, haloalkyl, aryl, heteroaryl, heteroarylalkyl, or arylalkyl;with the following provisos: (i) A is not a benz[c,d]indole; (ii) R³ orR⁴ is not

 if the other of R³ or R⁴ is hydrogen; and (iii) formula (I) is not


2. A compound of claim 1, including all stereoisomers thereof, or apharmaceutically acceptable salt thereof, wherein A is optionallysubstituted phenyl.
 3. A compound of claim 2, including allstereoisomers wherein R², R³ and R⁴ are independently hydrogen,C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆arylalkyl, C₁₋₆heteroarylalkyl,C₂₋₆alkenyl, or C₂₋₆alkynyl, wherein the heteroaryl or aryl component ofthe C₁₋₆arylalkyl and C₁₋₆heteroarylalkyl groups is optionallysubstituted.
 4. A compound having formula (II),

including all stereoisomers thereof, wherein: B is aryl or heteroaryl,each of which is optionally substituted; R¹ is (i) hydrogen, COR⁹,CO₂R⁹, SO₂R⁹, S(O)R⁹, or CONR⁷R⁸; or (ii) C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆heteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, eachgroup of which is optionally substituted; R², R³ and R⁴ areindependently hydrogen, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆arylalkyl,C₁₋₆heteroarylalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, or allyl, wherein theheteroaryl or aryl component of the C₁₋₆heteroarylalkyl andC₁₋₆arylalkyl groups is optionally substituted, R⁷ and R⁸ areindependently (i) hydrogen, COR⁹, SO₂R⁹, or S(O)R⁹ (ii) C₁₋₆alkyl,C₁₋₆heteroalkyl C₁₋₆haloalkyl, aryl, heteroaryl, allyl, or arylalkyl,each group of which is optionally substituted; T¹ through T⁵ areindependently (i) hydrogen, F, Cl, Br, I, NO₂, CN, OR⁹, or SR⁹; or (ii)C₁₋₆alkyl or C₁₋₆heteroalkyl, each group of which is optionallysubstituted; and R⁹ is hydrogen, C₁₋₆alkyl, heteroalkyl, haloalkyl,aryl, heteroaryl, or arylalkyl; with the following proviso: (i) formula(II) is not


5. A compound of claim 4, including all stereoisomers thereof, wherein Bis an optionally substituted phenyl ring.
 6. A compound of claim 5,including all stereoisomers thereof, wherein R¹ is hydrogen orC₁₋₆alkyl.
 7. A compound of claim 5, including all stereoisomersthereof, wherein T¹ through T⁵ is independently selected from H, F, Cl,Br, I, and —OC₁₋₆alkyl.
 8. A compound having formula (III),

including all stereoisomers thereof, wherein: R³ and R⁴ areindependently hydrogen, C₁₋₆alkyl, C₁₋₆heteroalkyl, C₁₋₆arylalkyl,C₁₋₆heteroarylalkyl C₂₋₆alkenyl, C₂₋₆alkynyl, or allyl, wherein theheteroaryl or aryl component of the C₁₋₆heteroarylalkyl andC₁₋₆arylalkyl groups is optionally substituted; T¹ through T¹⁰ areindependently (i) hydrogen, F, Cl, Br, I, NO₂, CN, OR⁹, or SR⁹; or (ii)C₁₋₆alkyl or C₁₋₆heteroalkyl, each group of which is optionallysubstituted; and R⁹ is hydrogen, C₁₋₆alkyl, heteroalkyl, haloalkyl,aryl, heteroaryl heteroarylalkyl, or arylalkyl; with the proviso that ifT⁸ is fluoro and T⁶, T⁷, T⁹ and T¹⁰ are all hydrogen then T¹ and T³cannot both be chloro if T², T⁴, and T⁵ are all hydrogen.
 9. A compoundof claim 8, including all stereoisomers thereof, wherein T¹ through T¹⁰are selected independently from hydrogen, F, Cl, Br I, and —OC₁₋₆alkyl.10. A compound of claim 9, including all stereoisomers, thereof, whereinR³ and R⁴ are selected independently from hydrogen and C₁₋₆alkyl.
 11. Acompound of claim 10, including all stereoisomers thereof, wherein R⁴ ishydrogen and R³ is C₁₋₆alkyl.
 12. A compound selected from: (i)

(ii) or a stereoisomer thereof.
 13. A pharmaceutical compositioncomprising a compound as defined in claim 1 and a pharmaceuticallyacceptable carrier thereof.
 14. A pharmaceutical combination comprisinga compound as defined in claim 1 and an immunosuppressant, an anticanceragent, an anti-viral agent, an anti-inflammatory agent, an anti-fungalagent, an anti-biotic, an anti-vascular hyperproliferation agent, ananti-depressant agent, a lipid-lowering agent, a lipid modulating agent,an antidiabetic agent, an anti-obesity agent, an antihypertensive agent,a platelet aggregation inhibitor and/or an antiosteoporosis agent,wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, asulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γdual agonist, an SGLT2 inhibitor, a DP4 inhibitor, an aP2 inhibitor, aninsulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and/or ameglitinide; the anti-obesity agent is a beta 3 adrenergic agonist, alipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, athyroid receptor agonist, an aP2 inhibitor or an anorectic agent; thelipid lowering agent is an MTP inhibitor, an HMG CoA reductaseinhibitor, a squalene synthetase inhibitor, a fibric acid derivative, anupregulator of LDL receptor activity, a lipoxygenase inhibitor or anACAT inhibitor; and the antihypertensive agent is an ACE inhibitor,angiotensin II receptor antagonist, NEP/ACE inhibitor, calcium channelblocker or β-adrenergic blocker.
 15. The combination as defined in claim14 wherein the antidiabetic agent is 1, 2, 3 or more of metformin,glyburide, glimepiride, glipyride, glipizide, chlorpropamide,gliclazide, acarbose, miglitol, pioglitazone, troglitazone,rosiglitazone, insulin, G1-262570, isaglitazone, JTT-501, NN-2344,L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129,AR-HO39242, GW-409544, KRP297, AC2993, LY315902, P32/98 and/orNVP-DPP-728A; the anti-obesity agent is selected from orlistat, ATL-962,AJ9677, L750355, CP331648, sibutramine, topiramate, axokine,dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol; thelipid lowering agent is pravastatin, lovastatin, simvastatin,atorvastatin, cerivastatin, fluvastatin, itavastatin, visastatin,fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700,cholestagel, niacin and/or LY295427; the antihypertensive agent is anACE inhibitor which is captopril, fosinopril, enalapril, lisinopril,quinapril, benazepril, fentiapril, ramipril or moexipril; an NEP/ACEinhibitor which is omapatrilat, [S[(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino[-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (gemopatrilat) or CGS 30440 or an angiotensin II receptorantagonist which is irbesartan, losartan or valsartan; amlodipinebesylate, prazosin HCl, verapamil, nifedipine, nadolol, propranolol,carvedilol or clonidine HCl ; and the platelet aggregation inhibitor isaspirin, clopidogrel, ticlopidine, dipyridamole or ifetroban.
 16. Thecombination as defined in claim 15 wherein the immunosuppressant is acyclosporin, mycophenolate, interferon-beta, deoxyspergolin, FK-506 orAnt.-IL-2; the anti-cancer agent is azathiprine, 5-fluorouracel,cyclophosphamide, cisplatin, methotrexate, thiotepa, or carboplatin; theanti-viral agent is abacavir, aciclovir, ganciclovir, zidanocin, orvidarabine; and the antiinflammatory drug is ibuprofen, celecoxib,rofecoxib, aspirin, naproxen, ketoprofen, diclofenac sodium,indomethacin, piroxicam, prednisone, dexamethasone, hydrocortisone, ortriamcinolone diacetate.